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      Athymic mice reveal a requirement for T-cell–microglia interactions in establishing a microenvironment supportive of Nf1 low-grade glioma growth

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          Abstract

          Murine Neurofibromatosis-1 ( Nf1) optic low-grade glioma (LGG) stem cells (o-GSCs) form glioma-like lesions in wild-type, but not athymic, mice following transplantation. Here, Pan et al. show that the inability of athymic mice to support o-GSC engraftment results from impaired brain microglia/macrophage function, including reduced expression of Ccr2 and Ccl5, both of which are required for o-GSC engraftment and Nf1 optic glioma growth.

          Abstract

          Pediatric low-grade gliomas (LGGs) frequently do not engraft in immunocompromised mice, limiting their use as an experimental platform. In contrast, murine Neurofibromatosis-1 ( Nf1) optic LGG stem cells (o-GSCs) form glioma-like lesions in wild-type, but not athymic, mice following transplantation. Here, we show that the inability of athymic mice to support o-GSC engraftment results from impaired microglia/macrophage function, including reduced expression of Ccr2 and Ccl5, both of which are required for o-GSC engraftment and Nf1 optic glioma growth. Impaired Ccr2 and Ccl5 expression in athymic microglia/macrophages was restored by T-cell exposure, establishing T-cell–microglia/macrophage interactions as critical stromal determinants that support NF1 LGG growth.

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          A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease.

          Hadas Keren‐Shaul, Amit Spinrad, Assaf Weiner … (2017)
          Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aβ particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)(-/-) Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases. VIDEO ABSTRACT.
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            The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases

            Scott T. Smith, Rachid El Fatimy, Ron Cialic … (2017)
            Microglia play a pivotal role in maintenance of brain homeostasis, but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Alzheimer’s disease (AD) and in microglia surrounding neuritic β-amyloid (Aβ) -plaques in human AD brains. The APOE pathway mediated a switch from a homeostatic to neurodegenerative microglia phenotype following phagocytosis of apoptotic neurons. Triggering receptor expressed on myeloid cells 2 (TREM2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia led to a loss in their tolerogenic function. Taken together, our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target to restore homeostatic microglia. Microglia change their phenotype and function during aging and neurodegeneration, but the underlying molecular mechanisms for this change remain unknown. Krasemann, Madore, et al. identify the TREM2-APOE pathway as a major regulator of microglia phenotypic change in neurodegenerative diseases, which may serve as a target to restore homeostatic microglia.
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              Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma.

              Zhihong Chen, Xi Kang Feng, Cameron J Herting … (2017)
              In glioblastoma (GBM), tumor-associated macrophages (TAM) represent up to one half of the cells of the tumor mass, including both infiltrating macrophages and resident brain microglia. In an effort to delineate the temporal and spatial dynamics of TAM composition during gliomagenesis, we used genetically engineered and GL261-induced mouse models in combination with CX3CR1(GFP/WT);CCR2(RFP/WT) double knock-in mice. Using this approach, we demonstrated that CX3CR1(Lo)CCR2(Hi) monocytes were recruited to the GBM, where they transitioned to CX3CR1(Hi)CCR2(Lo) macrophages and CX3CR1(Hi)CCR2(-) microglia-like cells. Infiltrating macrophages/monocytes constituted approximately 85% of the total TAM population, with resident microglia accounting for the approximately 15% remaining. Bone marrow-derived infiltrating macrophages/monocytes were recruited to the tumor early during GBM initiation, where they localized preferentially to perivascular areas. In contrast, resident microglia were localized mainly to peritumoral regions. RNA-sequencing analyses revealed differential gene expression patterns unique to infiltrating and resident cells, suggesting unique functions for each TAM population. Notably, limiting monocyte infiltration via genetic Ccl2 reduction prolonged the survival of tumor-bearing mice. Our findings illuminate the unique composition and functions of infiltrating and resident myeloid cells in GBM, establishing a rationale to target infiltrating cells in this neoplasm. Cancer Res; 77(9); 2266-78. ©2017 AACR.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Genes Dev
                Journal ID (iso-abbrev): Genes Dev
                Journal ID (hwp): genesdev
                Journal ID (pmc): genesdev
                Journal ID (publisher-id): GAD
                Title: Genes & Development
                Publisher: Cold Spring Harbor Laboratory Press
                ISSN (Print): 0890-9369
                ISSN (Electronic): 1549-5477
                Publication date (Print): 1 April 2018
                Volume: 32
                Issue: 7-8
                Pages: 491-496
                Affiliations
                [1 ]Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
                [2 ]Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
                [3 ]Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin 13125, Germany;
                [4 ]Genome Engineering and iPSC Center (GEIC), Washington University School of Medicine, St. Louis, Missouri 63110, USA;
                [5 ]Division of Neuropathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
                Author notes
                [6]

                These authors contributed equally to this work.

                Corresponding author: gutmannd@ 123456wustl.edu
                Author information
                http://orcid.org/0000-0002-3127-5045
                Article
                Medline ID: 8711660
                DOI: 10.1101/gad.310797.117
                PMC ID: 5959233
                PubMed ID: 29632086
                SO-VID: 69a878fe-9451-4cb4-a9da-93f4ac05d915
                Copyright © © 2018 Pan et al.; Published by Cold Spring Harbor Laboratory Press
                License:

                This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Date received : 12 December 2017
                Date accepted : 13 March 2018
                Page count
                Pages: 6
                Funding
                Funded by: National Institutes of Health , open-funder-registry 10.13039/100000002;
                Award ID: 1-R01-CA195692-01
                Award ID: 1-R35-NS07211-01
                Award ID: P30-CA91942
                Award ID: UL1-TR000448
                Funded by: James S. McDonnell Foundation , open-funder-registry 10.13039/100000913;
                Funded by: Berlin Institute of Health-Einstein
                Categories
                Subject: Research Communication

                Keywords: tumor microenvironment,stroma,monocyte,chemokines
                Data availability:
                Keywords: tumor microenvironment, stroma, monocyte, chemokines

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